WO2023216361A1 - Poct微流控芯片、检测系统、检测方法以及应用 - Google Patents

Poct微流控芯片、检测系统、检测方法以及应用 Download PDF

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Publication number
WO2023216361A1
WO2023216361A1 PCT/CN2022/098876 CN2022098876W WO2023216361A1 WO 2023216361 A1 WO2023216361 A1 WO 2023216361A1 CN 2022098876 W CN2022098876 W CN 2022098876W WO 2023216361 A1 WO2023216361 A1 WO 2023216361A1
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Prior art keywords
pool
reaction
poct
sample
microfluidic chip
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PCT/CN2022/098876
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English (en)
French (fr)
Inventor
刘俞超
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合肥诺迈基生物科技有限公司
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Priority to EP22941309.1A priority Critical patent/EP4393592A1/en
Publication of WO2023216361A1 publication Critical patent/WO2023216361A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/141—Preventing contamination, tampering
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers

Definitions

  • the invention belongs to the technical field of POCT detection using molecular diagnostic technology, and particularly relates to a POCT microfluidic chip, a POCT detection system including the POCT microfluidic chip, and molecular diagnostic technology POCT detection based on the POCT microfluidic chip.
  • the method also involves the application of the POCT microfluidic chip.
  • POCT point-of-care test testing refers to a testing method that uses portable analytical instruments and supporting reagents to quickly obtain test results at the sampling site.
  • the meaning of POCT can be understood from two aspects: spatially, the test is performed next to the patient, that is, "bedside test”; temporally, it can be "point-of-care test”.
  • the main criteria of POCT are that it does not require a fixed testing location, the reagents and instruments are portable, and can be operated in a timely manner. It has the advantages of speed, simplicity of use, and overall cost savings.
  • PCR polymerase chain reaction
  • various large-scale multi-functional PCR detection equipment can be seen everywhere, making outstanding contributions to the global fight against the epidemic; however, , as a powerful detection method, how to realize convenient detection and enter thousands of households is a challenge to contemporary scientific researchers.
  • microfluidic chip technology Born from application Microfluidics is characterized by the manipulation of fluids in micro- and nanoscale spaces.
  • the current POCT products basically use chromatographic immunoassay in the technical route.
  • the RGB color displayed after the reaction is read to identify the information. It is mainly used to detect heart disease. Rapid diagnosis of cerebrovascular and heart diseases; however, this type of technical solution is relatively mature and old. It only provides qualitative judgment and cannot be accurately quantified. It often requires further quantitative testing to achieve precise treatment effects.
  • the real-time fluorescence quantitative PCR detection technology solution can determine All molecular components can be accurately detected, and their content can be accurately detected, which is an accurate detection method that cannot be achieved by immunoassay.
  • Sample pool used to collect samples to be tested and lyse the samples to be tested
  • a mixed liquid pool which is connected to the sample pool through a microfluidic channel and is used to extract target fragments from the lysed sample to be tested;
  • a waste liquid pool which is connected to the mixed liquid pool and is used to collect waste liquid generated during the extraction process of the target fragment
  • reaction tank is connected to the mixed liquid tank through a microfluidic channel, wherein the reaction tank includes at least two independent constant temperature chambers, a superconducting thermal body is embedded at the bottom of the constant temperature chamber, and each constant temperature chamber The temperature is different, and the constant temperature chambers are connected through micro-fluidic channels.
  • Each constant-temperature room is equipped with an air bag pool, and the air bag pool is connected to the corresponding constant temperature chamber through micro-fluidic channels;
  • the sample pool, mixed liquid pool, waste liquid pool and reaction pool are all located on the lower housing, and a number of sampling ports are provided on the upper housing, which are connected to the sample pool, mixed liquid pool respectively. Corresponds to the reaction pool.
  • the sample pool is provided with a lysis absorption and release piece for absorbing and releasing the sample to be tested and the lysis solution to fully contact and lyse them.
  • the sample adding port of the sample pool is sealed with an antifouling component.
  • a software insert is provided on the surface of the upper housing, and the software insert is used to cut off the connection between the reaction tank, the mixed liquid tank, and the external environment.
  • the material of the software insert is selected from a combination of TPE, TPR, PU or silicone.
  • the air bag pool includes a pool body and a pressing air bag.
  • the pool body is provided in the lower shell.
  • the pressing air bag is embedded in the upper shell and corresponds to the pool body. By pressing The pressing air bag drives the flow of liquid in the corresponding constant temperature chamber.
  • the present invention further provides a POCT detection system, which includes POCT detection equipment and the POCT microfluidic chip as mentioned above.
  • the present invention further provides a POCT detection method based on the above-mentioned POCT microfluidic chip, which is characterized in that it includes the following steps:
  • the present invention has the following beneficial effects:
  • the POCT microfluidic chip in the present invention has a simple structure and low cost. It can greatly simplify the design of temperature control of auxiliary equipment and is low in cost, thereby greatly reducing the temperature control cost required for cyclic amplification reactions and is suitable for promotion. .
  • Figure 2 is a schematic diagram of the exploded structure of the POCT microfluidic chip in Figure 1;
  • FIG. 4 is a schematic structural diagram of the upper housing 10 in FIG. 2 .
  • the lower housing 20 is provided with a sample pool 21, a mixed liquid pool 22, a waste liquid pool 23 and a reaction pool 24.
  • the specific positions can be adjusted according to actual needs. There is no special requirement. limited.
  • the reaction pool 24 includes at least two independent constant temperature chambers. The number of constant temperature chambers is adjusted according to the temperature stages required for the actual reaction. It can be 2, 3, 4, etc., such as conventional cyclic amplification reactions in this field. Generally, if two or three different temperature reactions are required, 2 or 3 constant temperature chambers can be set up at this time.
  • the reaction pool 24 includes a first constant temperature chamber 241, a second constant temperature chamber 243 and a third constant temperature chamber 245, and the temperatures of the three constant temperature chambers are different. , thereby achieving the temperature control required in different reaction stages.
  • each constant temperature chamber is equipped with a corresponding airbag pool, as shown in Figure 3, which are a first airbag pool 242, a second airbag pool 244 and a third airbag pool 246 respectively.
  • Each airbag pool is connected to the airbag pool through a microfluidic channel.
  • each constant temperature chamber is connected to each other, and each constant temperature chamber is connected to each other through micro-fluidic channels, so that the flow of liquid between each constant temperature chamber can be controlled through the air bag pool.
  • FIG 4. There are multiple sampling ports on the upper housing 10, corresponding to the sample pool 21, the mixed liquid pool 22, the waste liquid pool 23 and the reaction pool 24. The specific number and position of the sampling ports can be Adjust according to each specific location and needs.
  • the sample pool 21 is used to collect the sample to be tested and lyse the sample to be tested.
  • the sample pool 21 is provided with a lysis absorption and release cotton 211.
  • the lysis absorption and release cotton 211 has a hydrophilic effect and is used to absorb the sample to be tested and the lysis solution, so that the sample to be tested and the lysis solution Full contact lysis.
  • the lysis absorbent cotton 211 can also have a lysis effect, thereby allowing the sample to be tested to be more fully lysed.
  • the fixing method of the pyrolysis, absorption and release cotton 211 is not particularly limited.
  • the mixing tank 22 is connected to the sample tank 21 through a microfluidic channel.
  • the mixing tank 22 is used to further cleave the mixture of the sample to be tested, and perform the lysis on the sample mixture to be tested. Extraction of target fragments.
  • the sample mixture to be tested in the sample pool 21 is continuously cracked while entering the mixing pool 22 through the microfluidic channel to ensure the adequacy of the cracking.
  • the magnetic bead method is used to extract target fragments from the sample to be tested in the mixing tank 22.
  • the upper housing 10 corresponding to the position of the mixing tank 22 is provided with a washing liquid adding port 104,
  • the eluent addition port 105, the magnetic bead solution addition port 106, and the pressurized exhaust hole 107 are used to add the required amount of liquid into the mixing tank 22 through the washing solution addition port 104, the eluent addition port 105, and the magnetic bead solution addition port 106.
  • Washing liquid, eluent and magnetic bead liquid, and the pressurized exhaust hole 107 is used to pressurize the mixing tank 22 to drive the flow of fluid through pressure.
  • the waste liquid tank 23 and the mixed liquid tank 22 are connected through microfluidic channels, and the number of connected microfluidic channels is not particularly limited.
  • the waste liquid pool 23 is used to collect the waste liquid generated during the target fragment extraction process in the mixed liquid pool 22 .
  • the upper housing 10 corresponding to the position of the waste liquid pool 23 is provided with an exhaust hole 108, which is used to discharge the waste liquid generated by the chip during the reaction process and guide it to the gas space eliminated during the waste liquid pool process. .
  • the reaction tank 24 includes a first constant temperature chamber 241, a second constant temperature chamber 243 and a third constant temperature chamber 245.
  • the first constant temperature chamber 241 and the mixed liquid tank 22 pass through the microfluidic channel.
  • a diagnostic reagent inlet 109 is provided on the upper housing 10.
  • the diagnostic reagent inlet 109 is connected to the first constant temperature chamber 241 through a microfluidic channel. Diagnostic reagents are added into the first constant temperature chamber 241 through the diagnostic reagent inlet 109.
  • the reagent is used to perform a cyclic amplification reaction at the first temperature stage with the target fragment.
  • the bottom of each constant temperature chamber is embedded with a superconducting heat body (not shown in the figure).
  • a cavity is provided on the lower housing 20, and a superconducting heat body is embedded at the bottom of the cavity.
  • the superconducting thermal body forms an independent constant temperature chamber with the upper shell 10 and the lower shell 20 respectively, wherein the superconducting thermal body is made of superconducting thermal material, and the superconducting thermal body
  • the material is a substance with a thermal conductivity >200W/m ⁇ °C and is inert to the reactants in each constant temperature chamber. The inertness means that the material does not react with the reactants in each constant temperature chamber.
  • the upper housing 10 is also provided with a software insert 110.
  • the software insert 110 corresponds to the diagnostic reagent inlet 109 and the microfluidic channel connecting the mixing tank 22 and the first constant temperature chamber 241.
  • the upper case 10 is provided with a hole for receiving the software insert 110 so that the software insert 110 is embedded in the upper case 10.
  • the software insert 110 is pressed, so that the software insert 110 is pressed.
  • the member 110 is pressed down to cut off the connection between the first thermostatic chamber 241 and the outside and the mixing tank 22, thereby avoiding aerosol pollution generated during the reaction.
  • the software insert 110 is made of soft plastic or colloid. Specific examples include but are not limited to combinations of TPE, TPR, PU or silicone. These soft materials can be used very well.
  • the reaction tank 24 is sealed.
  • the original solution of the sample to be tested is dropped from the sample inlet 101 onto the lysis absorption and release cotton 211 of the sample pool 21, and then the POCT microfluidic chip is inserted into the supporting equipment.
  • the operation program is set, the operation is started.
  • the supporting equipment first The sample to be tested and the lysis solution are pressed onto the lysis absorption and release cotton 211 through the sample inlet 101 and the lysis solution inlet 102 to cleave the sample to be tested.
  • the lysed sample mixture flows into the mixing tank 22 through the microfluidic channel, and then enters the mixed liquid.
  • the sample to be tested is continuously lysed;
  • the magnetic bead liquid adding port 106 can be opened to add the magnetic bead liquid into the mixing tank 22.
  • the supporting equipment provides vibration functions and heating functions to promote The lysis solution fully reacts with the sample to be tested, so that the DNA fragments are fully released and combined with the magnetic beads.
  • the electromagnetic strip of the auxiliary supporting equipment is energized, and the magnetic beads in the mixing tank 22 are adsorbed to the electromagnetic strip.
  • the supporting equipment provides vibration to promote the separation of DNA fragments and magnetic beads; then, the electromagnetic strip is opened again to adsorb the magnetic beads; the pressurized exhaust hole 107 provided on the mixed liquid pool 22 works again, and the pressing airbag of the first air bag pool 242 is loosened. Open (at this time, the pressing air bags of the second air bag pool 244 and the third air bag pool 246 are in the pressed state), add the DNA sample liquid in the mixed liquid pool 22 to the first thermostatic chamber 241 provided in the lower housing 20 for reaction. After the completion, the auxiliary equipment presses the first air bag pool 242 and releases the air bag of the second air bag pool 244 at the same time, forcing the reaction liquid to enter the second constant temperature chamber 243.
  • the reaction liquid obtains the reaction place.
  • the second stage reaction is carried out at the required temperature.
  • the auxiliary equipment will press the pressing air bag of the second air bag pool 244 and release the third air bag pool 246 at the same time, forcing the reaction liquid to enter the third constant temperature chamber 245.
  • the reaction solution obtains the temperature required for the reaction and performs the third stage reaction.
  • the photoelectric sensor probe collects the signal after the third reaction and transmits it to the software system for calculation and storage.
  • the supporting equipment described in this process is an automated instrument, which can be programmed to cooperate with the fluorescence detection chip to complete the entire detection process, which will not be described in detail here. Since each constant temperature chamber in this embodiment is an independent reaction chamber, the auxiliary equipment only needs to maintain the temperature of each constant temperature chamber through simple circuit design, and drive the reactants to be measured into the constant temperature chamber at the required temperature through the matching air bag pool. The reaction can be completed. Compared with the traditional temperature control method, the POCT microfluidic chip greatly reduces the cost, is more portable, and is easy to operate.
  • This embodiment further provides a POCT detection system, which at least includes POCT detection equipment and the above-mentioned POCT microfluidic chip, and may also include some automated operating equipment, control and result analysis modules, etc.
  • the POCT detection equipment can be used in conjunction with the POCT microfluidic chip. Specific examples that can be mentioned include but are not limited to some conventional detectors or detectors; the result analysis module includes but is not limited to computers and supporting Operation and analysis software, etc.
  • the present invention further discloses a POCT detection method, which includes the following steps:
  • the reaction signal in the constant temperature chamber of the final reaction is collected and transmitted to the analysis system, and the results are output after calculation and analysis.
  • the POCT microfluidic chip in the present invention can also be provided with at least one layer of housing on the upper housing 10 and the lower housing 20.
  • a multi-layer superposition structure such as 3 layers, 4 layers, etc.
  • each microfluidic channel or reaction chamber can be arranged in layers, thereby rationally optimizing the internal structure of the chip so that the microfluidic channels are independent of each other. Interference, and can communicate when needed, the specific structure can be adjusted according to the actual situation.
  • a number of through holes can be provided on the middle shell, and the micro-channels of each reaction chamber can be reasonably distributed through these through-holes to avoid mutual interference of the micro-channels.
  • the POCT microfluidic chip in the present invention can also detect multiple samples at the same time or multiple people for the same item.
  • the details can be adjusted according to actual needs and chip size, which will not be elaborated here.
  • the lower housing 20 can be provided with two sample pools 21, two mixed liquid pools 22, and a reaction pool 24 (the sample pools 21, the mixed liquid pool 22, and the reaction pool 24 are in a one-to-one correspondence), wherein, One of the mixing pools 22 is connected to the reaction pool 24 through a microfluidic channel; the other of the mixing pool 22 is connected to another reaction pool 24 through a microfluidic channel, thereby enabling one person to detect multiple samples, or multiple people to perform the same project. detection.

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Abstract

一种POCT微流控芯片、检测系统、检测方法以及应用；POCT微流控芯片包括上壳体(10)和下壳体(20)，还包括：样本池(21)、混液池(22)、废液池(23)以及反应池(24)，反应池(24)通过微流道与混液池(22)连接，其中，反应池(24)包括至少两个恒温室，每个恒温室的底部嵌有超导热体且各恒温室的温度不同，恒温室之间通过微流道相通；每个恒温室均配备有一气囊池，气囊池通过微流道与对应的恒温室相通。POCT微流控芯片使得反应液在各恒温的恒温室获取试剂反应所需温度，进行反应，最终达到获取反应后的各种信息。POCT微流控芯片除了实现目前QPCR的所有功能以外，具备操作简便，轻便小巧，成本低廉，检测迅捷，随时随地全员操作的优势。

Description

POCT微流控芯片、检测系统、检测方法以及应用 技术领域
本发明属于采用分子诊断技术的POCT检测技术领域，特别涉及一种POCT微流控芯片，包括该POCT微流控芯片的POCT检测系统，以及基于该POCT微流控芯片进行的分子诊断技术POCT检测方法，还涉及该POCT微流控芯片的应用。
 背景技术
POCT即时检验(point‑of‑care testing)指的是在采样现场进行的、利用便携式分析仪器及配套试剂快速得到检测结果的一种检测方式。POCT含义可从两方面进行理解：空间上，在患者身边进行的检验，即“床旁检验”；时间上，可进行“即时检验”。POCT的主要标准是不需要固定的检测场所，试剂和仪器是便携式的，并且可及时操作，其具有快速、使用简单和节约综合成本的优势。
目前，聚合酶链式反应（PCR）作为一种新兴技术，异军突起，成为分子诊断领域的主要模式，在当下，各种大型多功能PCR检测设备到处可见，为全球抗击疫情做出突出贡献；然而，作为一只强劲的检测手段方式，如何实现便民检测，走进千家万户，是对当代科研工作者的挑战，而作为一种精确控制和操控微尺度流体的技术，即微流控芯片技术运用而生：微流控（microfluidics）以在微纳米尺度空间中对流体进行操控为主要特征，具有将生物、化学等实验室的基本功能诸如样品制备、反应、分离和检测等缩微到一个几平方厘米芯片上的能力，其基本特征和最大优势在于多种单元技术在整体可控的微小平台上灵活组合、规模集成，涉及工程学、物理学、化学、微加工和生物工程等多个领域的学科交叉。
目前国内外采用PCR技术路线的POCT产品，几乎没有；当下的POCT产品，在技术路线上基本都是采用层析免疫法，读取反应后所呈现的RGB颜色来辨别信息，主要用来检测心脑血管及心脏疾病的快诊；而这类技术方案比较成熟老旧，只是定性判断，不能精准定量，往往需要进一步定量检测才能达到精准治疗效果；而实时荧光定量PCR检测技术方案，即可以判别所有分子成分，又可以精准检测出其含量，是免疫法无法实现精准检测手段；目前比较有代表性的属美国赛沛生物的GeneXpert系统，而此系统芯片也不具备核酸提取功能，且辅助设备较大，成本较高。此外，目前市面上所有的诊断试剂再进行循环扩增反应时都需要有温度要求，当循环扩增反应需要多个（如两个以上）温度进行反应时，对操作设备的要求比较高，尤其是对温控的要求较高，操作复杂且成本较高。
发明内容
有鉴于此，本发明有必要提供一种POCT微流控芯片，该POCT微流控芯片通过设计包括至少两个恒温室的反应池，且各个恒温室之间的温度不同，通过微流道将各个恒温室连通，使得反应液在各恒温的恒温室获取试剂反应所需温度，进行反应，最终达到获取反应后的各种信息。该POCT微流控芯片除了实现目前QPCR的所有功能以外，还具备操作简便，轻便小巧，成本低廉，检测迅捷，随时随地全员操作的优势。
为了实现上述目的，本发明采用以下技术方案：
本发明提供了一种POCT微流控芯片，包括上壳体和下壳体，还包括：
样本池，用于收集待测样本并对待测样本进行裂解；
混液池，其通过微流道与所述样本池连接，用于对裂解后的待测样本进行目标片段的提取；
废液池，其与所述混液池连接，用于收集目标片段提取过程中产生的废液；
以及反应池，所述反应池通过微流道与所述混液池连接，其中，所述反应池包括至少两个独立的恒温室，所述恒温室的底部嵌有超导热体且各恒温室的温度不同，恒温室之间通过微流道相通，每个恒温室均配备有一气囊池，所述气囊池通过微流道与对应的恒温室相通；
其中，所述样本池、混液池、废液池和反应池均设于所述下壳体上，且在所述上壳体上设有若干加样口，分别与所述样本池、混液池和反应池对应。
进一步方案，所述超导热体的材质选自金属、单晶硅或陶瓷。
进一步方案，所述样本池内设有裂解吸释件，用于吸释待测样本和裂解液，使之充分接触裂解。
进一步方案，所述样本池的加样口密封有防污件。
进一步方案，所述上壳体表面设有软体嵌件，所述软体嵌件用于截断所述反应池与混液池、外部环境的连接。
进一步方案，所述软体嵌件的材质选自TPE、TPR、PU或硅胶组合。
进一步方案，所述气囊池包括池体和按压气囊，所述池体设于所述下壳体中，所述按压气囊嵌设于所述上壳体中且与所述池体对应，通过按压所述按压气囊，驱动对应恒温室内液体的流动。
本发明进一步提供了一种POCT检测系统，包括POCT检测设备，还包括如前所述的POCT微流控芯片。
本发明进一步提供了一种基于上述的POCT微流控芯片进行的POCT检测方法，其特征在于，包括以下步骤：
向样本池中加入待测样本和裂解液，对待测样本进行裂解；
将裂解后的待测样本混合物引导至混液池内，采用磁珠法对待测样本进行目标片段的提取；
将提取后的目标片段引导至反应池中，同时向反应池内加入诊断试剂，待测样本混液根据反应所需的温度，在各自配备的气囊池的驱动下，进入各个恒温室中，进行各个阶段的循环反应；
采集反应池中最终反应的恒温室的反应信号，运算分析并输出结果。
本发明还提供了如前所述的POCT微流控芯片在核酸检测中的应用。
与现有技术相比，本发明具有以下有益效果：
本发明中的POCT微流控芯片结构简单，成本低廉，能够极大的简化辅助设备在温度控制上的设计，成本低廉，从而极大的降低循环扩增反应所需的温控成本，适宜推广。
 附图说明
图1为本发明一较佳实施例中POCT微流控芯片的结构示意图；
图2为图1中POCT微流控芯片的分解结构示意图；
图3为图2中下壳体20的结构示意图；
图4为图2中上壳体10的结构示意图。
图中：10-上壳体、101-样本加入口、102-裂解液加入口、103-加压孔、104-洗涤液加入口、105-洗脱液加入口、106-磁珠液加入口、107-加压排气孔、108-排气孔、109-诊断试剂加入口、110-软体嵌件；
20-下壳体、21-样本池、211-裂解吸释棉、22-混液池、23-废液池、24-反应池、241-第一恒温室、242-第一气囊池、2421-第一按压气囊、243-第二恒温室、244-第二气囊池、2441-第二按压气囊、245-第三恒温室、246-第三气囊池、2461-第三按压气囊；
30-防污贴纸。
具体实施方式
下面将结合说明书附图，对本发明中的POCT微流控芯片进行进一步的详细说明。
需要说明的是，当元件被称为“固定于”、“设置于”、“安装于”另一个元件，它可以是直接在另一个元件上或者间接在所述另一个元件上。但一个元件被称为“连接于”、“相连”另一个元件，它可以是直接连接到另一个元件或间接连接至所述另一个元件上。另外，连接一般指的是用于固定作用，这里的固定可以是本领域常规的任何一种固定方式，如“螺纹连接”、“铆接”、“焊接”等。
需要理解的是，术语“长度”、“宽度”、“上”、“下”、“前”、“后”、“左”、“右”、“竖直”、“水平”、“顶”、“底”、“内”、“外”等指示的方位或位置关系为基于说明书附图所示的方位或位置关系，仅是为了便于描述本发明实施例和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位，以特定的方位构造或操作，因此不能理解为对本发明的限制。
请参阅图1和图2，示出了一种POCT微流控芯片，其包括上壳体10和下壳体20，上壳体10和下壳体20通过本领域中常规的键合方式键合形成芯片整体，具体的键合工艺包括但不限于静电键合、热压键合或激光键合，没有特别的限定。其中，上壳体10和下壳体20的材质可以采用本领域中常规的选择，如高透光塑料、金属合金、非金属或其他混合材料等，需要特别说明的是，为了实现荧光检测的目的，上壳体10须采用高透光材质，而下壳体20则没有特别的限定，只要满足材料的生物兼容性好的材质均可用于下壳体20。进一步的，请结合图3，本实施例中，在下壳体20上设有样本池21、混液池22、废液池23和反应池24，具体的位置可根据实际需要进行调整，没有特别的限定。反应池24包括至少两个独立的恒温室，恒温室的数量根据实际反应所需要的温度阶段进行调整，可以为2个、3个、4个等，如本领域中常规的循环扩增反应，一般需要两个或三个不同温度反应，则此时可设置2个或3个恒温室。如图3所示的，在本实施例的POCT微流控芯片结构中，反应池24包括第一恒温室241、第二恒温室243和第三恒温室245，且三个恒温室的温度不同，从而实现不同反应阶段所需的温度控制。进一步的，各恒温室均配备有对应的气囊池，如图3所示的，其分别为第一气囊池242、第二气囊池244和第三气囊池246，各气囊池通过微流道与对应的恒温室相通，且各恒温室之间通过微流道相通，从而可通过气囊池控制液体在各恒温室之间的流动。此外，请结合图4，在上壳体10上设有多个加样口，分别对应于样本池21、混液池22、废液池23和反应池24，加样口具体的数量和位置可根据各具体的的位置和需要进行调整。
请继续参阅图2和图3，具体的说，样本池21用于收集待测样本并对待测样本进行裂解。如图2和3中所示的，样本池21内设有裂解吸释棉211，该裂解吸释棉211具有亲水作用，用于吸收待测样本和裂解液，使得待测样本与裂解液充分接触裂解，优选的，该裂解吸释棉211还可以具有裂解的作用，从而使得待测样本更充分的裂解。该裂解吸释棉211的固定方式没有特别的限定，具体的说，如图3中所示的本实施例在样本池21内设有立柱，将裂解吸释棉211插设于立柱上实现固定。进一步的，结合图4，在与样本池21位置对应的上壳体10上设有样本加入口101和裂解液加入口102，可通过样本加入口101和裂解液加入口102分别向样本池21中加入待测样本和裂解液，获得裂解后的样本混合物。通过将待测样本和裂解液分别通过不同的加样口加入样本池21中，可避免配套设备的添加裂解液的入口被待测样本污染。此外，本实施例中裂解液加入口102通过多条微流道连通样本池21，从而可以使得样本得到更加充分的裂解；如图4中所示的，在上壳体10上还设有加压孔103，用于通过外部加压设备进行加压，通过压力驱动裂解液进入样本池21内。
进一步的，如图1和2中所示的，在样本加入口101密封有防污贴纸30，该防污贴纸30将样本加入口101密封，一方面避免固定在样本池21中的裂解吸释棉211被外界污染，另一方面可在取样完成后再次将样本加入口101密封，避免外界环境的干扰，确保反应的精准性。需要注意的是，防污贴纸30具有粘性的一面不能够与待测样本等反应。
进一步的，请继续参阅图3，本实施例中，混液池22通过微流道与样本池21相连，混液池22用于对待测样本的混合物进一步裂解，并对裂解后的待测样本混合物进行目标片段的提取。样本池21内的待测样本混合物，通过微流道进入混液池22的过程中持续不断进行裂解，确保裂解的充分性。在本实施例中，在混液池22中采用磁珠法对待测样本进行目标片段的提取，结合图4，在与混液池22位置对应的上壳体10上分别设有洗涤液加入口104、洗脱液加入口105和磁珠液加入口106以及加压排气孔107，通过洗涤液加入口104、洗脱液加入口105和磁珠液加入口106向混液池22中加入所需的洗涤液、洗脱液和磁珠液，而加压排气孔107则用于对混液池22内加压通过压力驱动流体的流动。
进一步的，请继续参阅图3，废液池23与混液池22通过微流道连通，连通的微流道数量没有特别的限定。废液池23用于收集混液池22中目标片段提取过程中产生的废液。具体的，结合图4，与废液池23位置对应的上壳体10上设有排气孔108，用于排出芯片在反应过程中产生的废液引导至废液池过程中排除的气体空间。
进一步的，如图3所示的，本实施例中，反应池24包括第一恒温室241、第二恒温室243和第三恒温室245，第一恒温室241与混液池22通过微流道相通，在上壳体10上设有诊断试剂加入口109，该诊断试剂加入口109通过微流道与第一恒温室241连通，通过该诊断试剂加入口109向第一恒温室241内加入诊断试剂，与目标片段进行第一温度阶段的循环扩增反应。各恒温室的底部分别嵌有超导热体（图未示），具体的说，在下壳体20上设有凹腔，在凹腔的底部嵌有超导热体，通过上壳体10和下壳体20键合，从而使得超导热体分别与上壳体10、下壳体20形成独立的恒温室，其中，超导热体由超导热材料制成，所述的超导热材料为导热系数＞200W/m·℃且对各恒温室内的反应物呈惰性的物质，所述的惰性指的是该材料不与各恒温室内的反应物发生任何反应，具体的可通过对材料表面进行惰性氧化处理实现，该超导热材料可以选自金属、单晶硅或陶瓷。进一步的，各恒温室之间通过微流道相通，且各恒温室分别配备有一气囊池，如图中3所示的，第一气囊池242、第二气囊池244和第三气囊池246分别设于下壳体20上请结合图4，在上壳体10上分别设有与第一气囊池242、第二气囊池244和第三气囊池246分别对应的第一按压气囊2421、第二按压气囊2441和第三按压气囊2461，第一按压气囊2421、第二按压气囊2441和第三按压气囊2461为具有弹性的软体材料，如橡胶等，通过按压按压气囊，改变对应气囊池内的压力，从而驱动对应的恒温室内的液体流动。
进一步的，请参阅图4，在上壳体10上还设有软体嵌件110，该软体嵌件110与诊断试剂加入口109以及混液池22和第一恒温室241连接微流道相对应，具体的说，在上壳体10上设有收容软体嵌件110的孔洞，使得软体嵌件110嵌入上壳体10中，通过外部配套设备的配合，对软体嵌件110施压，使得软体嵌件110下压，从而切断第一恒温室241与外部以及混液池22的连接，可避免反应过程中产生的气溶胶污染。本实施例中，所述的软体嵌件110采用的为软质塑料或胶体，具体可提及的实例包括但不限于自TPE、TPR、PU或硅胶组合，采用这些软质材质能够很好的实现对反应池24的密闭。
本实施例中所述的POCT微流控芯片具体工作流程为：
将待测样本原液从样本加入口101滴入样本池21的裂解吸释棉211上，再将该POCT微流控芯片插入配套的设备上，设定好运行程序后开启运行，配套设备首先将待测样本和裂解液通过样本加入口101、裂解液加入口102压入到裂解吸释棉211上，对待测样本进行裂解，裂解的样本混合物通过微流道流入混液池22中，在进入混液池22的过程中，待测样本持续不断的进行裂解；
在样本混合液刚流入混液池22时，磁珠液加入口106即可开启向混液池22中加入磁珠液，待两种液体规定量完成加入后，配套设备提供振动功能和加热功能，促使裂解液与待测样本充分反应，使DNA片段释放充分，并与磁珠结合，待此程序结束后，对辅助配套设备的电磁条进行通电，将混液池22中的磁珠吸附在电磁条的周边；此时对设置在混液池22上的加压排气孔107进行加压（此时第一气囊池242、第二气囊池244和第三气囊池246的按压气囊按压状态），在压力驱动下将废液通过微流道排入废液池23；待废液排尽后，从洗脱液加入口105向混液池22中加入预定量的洗脱液，此时，关闭电磁条，配套设备提供振动，促使DNA片段与磁珠分离；随后，电磁条再次打开，将磁珠吸附；设置在混液池22上的加压排气孔107再次工作，第一气囊池242的按压气囊松开（此时第二气囊池244和第三气囊池246的按压气囊处于按压状态）将混液池22中的DNA样本液，加入设在下壳体20中的第一恒温室241中进行反应，反应结束后，辅助设备按压第一气囊池242按压气囊的同时，放开第二气囊池244的按压气囊，迫使反应液进入第二恒温室243，在第二恒温室243中，反应液获得反应所需的温度，进行第二阶段反应，在规定时间后，辅助设备将按压第二气囊池244的按压气囊，同时放开第三气囊池246，迫使反应液进入第三恒温室245中，在第三恒温室245中，反应液获取反应所需的温度，进行第三阶段反应，在规定时间后，光电感应探头将第三反应后的信号收集并传到软件系统进行运算储存，按同样的步骤，促使反应液在三个不同的恒温室间进行运转反应，并在每次第三个反应室将反应后的信号收集并传送到软件系统进行运算，并将最终的结果展示给客户。可以理解的是，该过程中所述的配套设备为自动化仪器，可通过程序设计配合该荧光检测芯片完成整套检测流程，这里不再具体阐述。由于本实施例中各恒温室均为独立的反应腔室，辅助设备仅需通过简单的电路设计分别维持各恒温室的温度，通过配套气囊池驱动待测反应物进入所需温度的恒温室中即可完成反应，相较于传统的温控方式，该POCT微流控芯片极大的降低了成本，且更加便携，操作简单。
本实施例进一步提供了一种POCT检测系统，该POCT检测系统至少包括POCT检测设备和上述的POCT微流控芯片，还可以包括一些自动化的操作设备以及控制及结果分析模块等。所述的POCT检测设备能够与POCT微流控芯片配套使用，具体可提及的实例包括但不限于一些常规的检测仪或检测器等；所述的结果分析模块包括但不限于计算机以及配套的操作、分析软件等。
基于本实施例中提供的POCT微流控芯片，本发明进一步公开了一种POCT检测方法，包括以下步骤：
向样本池中加入待测样本和裂解液，对待测样本进行裂解；
将裂解后的待测样本混合物引导至混液池内，采用磁珠法对待测样本进行目标片段的提取；
将提取后的目标片段引导至反应池中，同时向反应池内加入诊断试剂，通过气囊池控制液体流动在不同恒温室内进行各阶段反应；
采集最终反应的恒温室中的反应信号，并传输至分析系统内，运算分析后输出结果。
此外，作为变换，本发明中的POCT微流控芯片，除了可以为上壳体10和下壳体20形成的芯片结构，还可以在上壳体10和下壳体20设置至少一层壳体的多层叠加结构（如3层、4层等），通过设置多层叠加结构能够对各微流道或反应腔室分层设置，从而合理优化芯片内部结构，使得微流道之间相互不干涉，且在需要时能够相通，具体的结构可根据实际情况进行调整。具体的说，可在中壳体上设有若干通孔，将各反应腔室的微流道通过这些通孔合理分布，避免微流道相互干扰。
进一步的，本发明中的POCT微流控芯片还可以针对多份样本同时检测或同项目的多人份检测，具体可根据实际需要以及芯片尺寸进行调整，这里不再具体阐述。具体的说，可在在下壳体20上设有2个样本池21、2个混液池22和反应池24（样本池21、混液池22和反应池24为一一对应的关系），其中，混液池22的其中一个，通过微流道与反应池24连接；混液池22的另一个，通过微流道与另外的反应池24连接，从而实现一人多份样本的检测，或多人同项目的检测。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种POCT微流控芯片，包括上壳体和下壳体，其特征在于，还包括：
    样本池，用于收集待测样本并对待测样本进行裂解；
    混液池，其通过微流道与所述样本池连接，用于对裂解后的待测样本进行目标片段的提取；
    废液池，其与所述混液池连接，用于收集目标片段提取过程中产生的废液；
    以及反应池，所述反应池通过微流道与所述混液池连接，其中，所述反应池包括至少两个恒温室，每个恒温室的底部嵌有超导热体且各恒温室的温度不同，恒温室之间通过微流道相通；每个恒温室均配备有一气囊池，所述气囊池通过微流道与对应的恒温室相通；
    其中，所述样本池、混液池、废液池和反应池均设于所述下壳体上，且在所述上壳体上设有若干加样口，分别与所述样本池、混液池和反应池对应。
  2. 如权利要求1所述的POCT微流控芯片，其特征在于，所述超导热体的材质选自金属、单晶硅或陶瓷。
  3. 如权利要求1所述的POCT微流控芯片，其特征在于，所述样本池内设有裂解吸释件，用于吸释待测样本和裂解液，使之充分接触裂解。
  4. 如权利要求1所述的POCT微流控芯片，其特征在于，所述样本池的加样口密封有防污件。
  5. 如权利要求1所述的POCT微流控芯片，其特征在于，所述上壳体表面设有软体嵌件，所述软体嵌件用于截断所述反应池与混液池、外部环境的连接。
  6. 如权利要求5所述的POCT微流控芯片，其特征在于，所述软体嵌件的材质选自TPE、TPR、PU或硅胶组合。
  7. 如权利要求1所述的POCT微流控芯片，其特征在于，所述气囊池包括池体和按压气囊，所述池体设于所述下壳体中，所述按压气囊嵌设于所述上壳体中且与所述池体对应，通过按压所述按压气囊，驱动对应恒温室内液体的流动。
  8. 一种POCT检测系统，包括POCT检测设备，其特征在于，还包括如权利要求1-7所述的POCT微流控芯片。
  9. 一种基于权利要求1-7任一项所述的POCT微流控芯片进行的POCT检测方法，其特征在于，包括以下步骤：
    向样本池中加入待测样本和裂解液，对待测样本进行裂解；
    将裂解后的待测样本混合物引导至混液池内，采用磁珠法对待测样本进行目标片段的提取；
    将提取后的目标片段引导至反应池中，同时向反应池内加入诊断试剂，待测样本混液根据反应所需的温度，在各自配备的气囊池的驱动下，进入各个恒温室中，进行各个阶段的循环反应；
    采集反应池中最终反应的恒温室的反应信号，运算分析并输出结果。
  10. 如权利要求1-7任一项所述的POCT微流控芯片在核酸检测中的应用。
PCT/CN2022/098876 2022-05-07 2022-06-15 Poct微流控芯片、检测系统、检测方法以及应用 WO2023216361A1 (zh)

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